Membrane-permeable small organic molecules comprise the majority of current therapeutic agents. They are also used in the area of chemical biology to perturb and modulate the function of biomolecules in vitro and in vivo. Identification of new bioactive compounds often relies on screening of large collections of compounds, known as chemical libraries. Unlike the solid-phase synthesis of peptides, oligonucleotides and oligosaccharides, all of which have greatly advanced over the years, high-throughput synthesis of small-molecule libraries in high chemical purity remains to be a challenge. Several methods of generation of chemical libraries have been developed over the years. However, each of these methods suffers from several problems, which preclude their wide-spread applications in academics and pharmaceutical industry.
Solid-phase synthesis enables facile generation of molecular diversity, particularly via the split-and-pool method. For small-molecule libraries, however, this strategy suffers from the laborious process of reaction optimization and frequently results in moderate purities of the final compounds, once detached from the solid support. Low chemical purity results in large numbers of false positive hits in biological assays.
Solution-phase synthesis using soluble oligomeric or polymeric support requires derivatization and cleavage of each individual compound from such support. Significant amount of time is generally required for optimization of reaction conditions. While the solution-based approaches enable more rapid reaction optimization and higher chemical purities, these advances come at the expense of significantly higher costs, which arise from the use of polymer-supported reagents, the development of appropriate soluble polymeric supports, or the expensive instrumentation required for robotic chromatographic purification of the final compounds.
Another approach relies on parallel synthesis and robotically-driven automated HPLC purification of each individual compound. While reaction optimization is efficient and final products with high purity are produced, this strategy requires highly specialized equipment, and requires significant investment of resources and supplies.
It is thus desirable to develop a practical and general strategy for rapid and efficient generation of new small-molecule libraries in high chemical purity.